P585: IMPACT OF MYELOID MUTATION PROFILE ON PCR RESPONSES AND SURVIVAL IN PATIENTS WITH CORE-BINDING FACTOR AML TREATED WITH FLAG BASED REGIMES
Authors: Jayastu Senapati, Aram Bidikian, Farhad Ravandi, Tapan Kadia, Courtney Dinardo, Guillermo Garcia-Manero, Naval Daver, Naveen Pemmaraju, Elias Jabbour, Mark Brandt, Gautam Borthakur
Journal: HemaSphere (2023)

Background: Attainment of optimal reduction of disease defining translocation transcripts by PCR (OPR) among patients with acute myeloid leukemia (CBF-AML) has the most definitive impact on outcome. Baseline myeloid mutations including those in the kinase pathway, chromatin modifiers and cohesion complex could affect survival outcomes. The prognostic impact of kinase pathway mutations in patients treated with fludarabine, cytarabine, G-CSF (FLAG) based regimen is minimal (Senapati et al AJH, 2023), however the role of other myeloid mutations on molecular response and survival outcomes in CBF-AML patients treated with FLAG based regimens warrant evaluation. Aims: We aimed to study the impact of kinase and non-kinase myeloid mutations on OPR and survival outcomes in adult patients with CBF-AML treated with FLAG based regimens. Methods: We analyzed the myeloid mutational profile of a contemporary cohort (2017-2022) of adult patients with CBF-AML who had a complete 81-panel myeloid mutational data on NGS and were treated with FLAG based regimen with idarubicin (FLAG-IDA) or gemtuzumab ozogamicin (FLAG-GO). We analyzed the attainment of OPR (through quantification of CBF defining genetic aberrations) and survival of patients with different mutational profiles. Myeloid mutation was detected at a variable allele frequency of 2% and performed at our institutional CLIA certified lab. OPR was defined as <0.1% after induction and <0.01% anytime during/after consolidation, with the later time point being prognostically superior. Patients received up to 7 cycles of FLAG regimen. Results: From Jan 2017 to Dec 2022, 57 consecutive patients, with a median age of 55 years (range, 19-80), were treated for CBF-AML with FLAG-IDA (32%) or FLAG-GO (68%) regimens (Fig 1). Around a third (37%) of patients had t(8;21). Genetic mutations were grouped into kinase pathway (FLT3, KIT and RAS), DNA methylation, chromatin modifiers, transcription factors, cohesion complex and tumor suppressor families. There were no patients with splicing factor gene mutations. Forty-seven (82%) patients had a kinase mutation, 10 (21%) of whom had other concurrent mutations. Only 4 patients (7%) had a myeloid mutation without a concurrent kinase pathway mutation and overall, 6 patients (10%) had no mutations. Fifty-six of 57 (98%) patients attained a complete remission as best response; OPR post C1 was attained in 35 of 52 (67%) evaluable patients and later OPR in 37 of 43 (86%) evaluable patients. Amongst 37 patients with only kinase pathway mutations, 26/33 (79%) evaluable patients attained a later OPR; of 14 patients with other myeloid mutations (+/- kinase pathway mutations), 10/13 evaluable (80%) attained this endpoint (p=0.9). All evaluable patients without any mutation had a later OPR. At a median follow up of 33 months, the median RFS and OS were similar and not reached for patients with only kinase pathway mutations, other myeloid mutations and no mutations (Figure 1). Summary/Conclusion: In CBF AML patients treated with FLAG based regimens, concurrent myeloid mutations do not have a significant prognostic impact. Further myeloid genotyping on a larger cohort of patients with CBF-AML is underway. Keywords: Minimal residual disease (MRD), Core binding factor leukemia, Fludarabine, Acute myeloid leukemia